RBD Subjects Research Articles

Progressive Olfactory Impairment and Cardiac Sympathetic Denervation in REM Sleep Behavior Disorder.

Background:Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB).Objective:We investigated the use of cardiac [123I]meta-iodo-benzyl-guanidine scintigraphy ([123I]MIBG) and olfactory testing— in comparison to [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single photon emission computed tomography ([123I]FP-CIT-SPECT)— for identifying iRBD patients as prodromal phenotype of PD/DLB.Methods:37 RBD subjects underwent cardiac [123I]MIBG and brain [123I]FP-CIT-SPECT at baseline. Olfactory (Sniffin’ Sticks), cognitive and motor functions were tested annually for ∼4 years.Results:29/37 (78.4%) subjects had a pathological [123I]MIBG, of whom 86.2% (25/29) presented at least a moderate hyposmia at baseline (threshold/discrimination/identification-(TDI-)score ≤25). 20/37 (54.1%) subjects had a pathological [123I]FP-CIT-SPECT, always combined with a pathological [123I]MIBG. In subjects with pathological [123I]MIBG, olfactory function worsened (mainly due to threshold and discrimination subscores) from baseline to follow-up (p = 0.005). Olfaction was more impaired in subjects with pathological [123I]MIBG compared to those with normal [123I]MIBG at baseline (p = 0.001) and follow-up (p < 0.001). UPDRS-III scores increased in subjects with both pathological [123I]MIBG and [123I]FP-CIT-SPECT. In this group, seven subjects phenoconverted to PD, all— except for one— presented with at least moderate hyposmia at baseline.Conclusion:A combination of the biomarkers “pathological [123I]MIBG” and “hyposmia” likely identifies iRBD patients in an early prodromal stage of PD/DLB, i.e., before nigrostriatal degeneration is visualized. One-third of the subjects with pathological [123I]MIBG had a normal [123I]FP-CIT-SPECT. Noteworthy, in iRBD subjects with pathological [123I]MIBG, olfactory impairment is progressive independent of the [123I]FP-CIT-SPECT status.

Assessing REM Sleep Behaviour Disorder: From Machine Learning Classification to the Definition of a Continuous Dissociation Index.

Objectives: Rapid Eye Movement Sleep Behaviour Disorder (RBD) is regarded as a prodrome of neurodegeneration, with a high conversion rate to –synucleinopathies such as Parkinson’s Disease (PD). The clinical diagnosis of RBD co–exists with evidence of REM Sleep Without Atonia (RSWA), a parasomnia that features loss of physiological muscular atonia during REM sleep. The objectives of this study are to implement an automatic detection of RSWA from polysomnographic traces, and to propose a continuous index (the Dissociation Index) to assess the level of dissociation between REM sleep stage and atonia. This is performed using Euclidean distance in proper vector spaces. Each subject is assigned a dissociation degree based on their distance from a reference, encompassing healthy subjects and clinically diagnosed RBD patients at the two extremes. Methods: Machine Learning models were employed to perform automatic identification of patients with RSWA through clinical polysomnographic scores, together with variables derived from electromyography. Proper distance metrics are proposed and tested to achieve a dissociation measure. Results: The method proved efficient in classifying RSWA vs. not-RSWA subjects, achieving an overall accuracy, sensitivity and precision of 87%, 93% and 87.5%, respectively. On its part, the Dissociation Index proved to be promising in measuring the impairment level of patients. Conclusions: The proposed method moves a step forward in the direction of automatically identifying REM sleep disorders and evaluating the impairment degree. We believe that this index may be correlated with the patients’ neurodegeneration process; this assumption will undergo a robust clinical validation process involving healthy, RSWA, RBD and PD subjects.

CSF and plasma biomarkers for DLB

AbstractBackgroundCSF biomarkers of amyloid and tau provide components of the A/T/N classification for AD and hold clinical prognostic value. They can help to identify how AD co‐pathology contributes to DLB. Alpha‐synuclein (a‐Syn) aggregation is a key pathogenic process in DLB, proposed to follow a staging system for spread of pathology. We review existing CSF markers in DLB and evaluate how well RT‐QuIC, a protein misfolding amplification assay for a‐Syn, detects DLB and different degrees of a‐Syn pathology at autopsy, and performs in RBD, a prodromal stage of DLB. We discuss the potential for plasma biomarkers for diagnosis and progression in DLB.Method1) selected studies of CSF biomarker data from RBD subjects and from published data for DLB on A/T/N biomarkers and on a‐Syn RT‐QuIC and other a‐Syn biomarkers; 2) analysis of different parameters of a‐synuclein RT‐QuIC and clinical‐pathological correlations for RT‐QuIC; 3) data on plasma neurofilament light as a progression biomarker.Result1) AD biomarkers in CSF support AD co‐pathology in a substantial percentage of cases of DLB, which is associated with faster cognitive progression. Data on RBD and prodromal DLB are limited. 2) RT‐QUiC has high sensitivity and specificity for PD and DLB diagnosis, including RBD. RT‐QuIC parameters (time to 50% of maximal fluorescence or peak fluorescence) do not correlate with measures of movement or cognition. Limiting dilution may provide an index of seeding burden, but in preliminary analyses shows a weak relationship to clinical progression; 3) longitudinal Nfl plasma levels in the PPMI cohort show a slight increase in early PD and RBD, to a greater extent than in aging alone, with much overlap. Concomitant AD pathology may drive plasma Nfl changes.ConclusionCSF biomarkers related to neurodegeneration may provide value in early DLB. CSF Aβ1‐42/Tau has prognostic value for cognitive decline in DLB. RT‐QuIC for a‐synuclein in CSF has diagnostic but not predictive value. Plasma biomarkers for diagnosis of pathology are emerging, but prognostic markers will need extensive additional research.

Convergent patterns of structural brain changes in rapid eye movement sleep behavior disorder and Parkinson's disease on behalf of the German rapid eye movement sleep behavior disorder study group.

Rapid eye movement sleep behavior disorder (RBD) is considered a prodromal state of Parkinson's disease (PD). We aimed to characterize patterns of structural brain changes in RBD and PD patients using multimodal MRI. A total of 30 patients with isolated RBD, 29 patients with PD, and 56 age-matched healthy controls (HC) underwent MRI at 3T, including tensor-based morphometry, diffusion tensor imaging, and assessment of cortical thickness. RBD individuals showed increased volume of the right caudate nucleus compared with HC, and higher cerebellar volume compared with both PD subjects and HC. Similar to PD subjects, RBD patients displayed increased fractional anisotropy (FA) in the corticospinal tracts, several tracts mainly related to non-motor function, and reduced FA of the corpus callosum compared with HC. Further, RBD subjects showed higher FA in the cerebellar peduncles and brainstem compared with both, PD patients and HC. PD individuals exhibited lower than normal volume in the basal ganglia, midbrain, pedunculopontine nuclei, and cerebellum. In contrast, volume in PD subjects was increased in the thalamus compared with both HC and RBD subjects. We found convergent patterns of structural brain alterations in RBD and PD patients compared with HC. The changes observed suggest a co-occurrence of neurodegeneration and compensatory mechanisms that fail with emerging PD pathology. Our findings strengthen the hypothesis of RBD and PD constituting a continuous disease spectrum.

Instrumental analysis of finger tapping reveals a novel early biomarker of parkinsonism in idiopathic rapid eye movement sleep behaviour disorder

BackgroundIdiopathic rapid eye movement sleep behaviour (iRBD) is considered as a risk factor for Parkinson's disease (PD) development. Evaluation of repetitive movements with finger tapping, which serves as a principal task to measure the extent of bradykinesia in PD, may undercover potential PD patients. The aim of this study was to explore whether finger tapping abnormalities, evaluated with a 3D motion capture system, are already present in RBD patients. MethodsFinger tapping data was acquired using a contactless 3D motion capture system from 40 RBD subjects and compared to 25 de-novo PD patients and 25 healthy controls. Objective assessment of amplitude decrement, maximum opening velocity and their combination representing finger tapping decrement was performed in the sequence of the first ten tapping movements. The association between instrumental finger tapping data and semi-quantitative clinical evaluation was analyzed. ResultsWhile significant differences between PD and controls were found for all investigated finger tapping measures (p < 0.002), RBD differed from controls in finger tapping amplitude (p = 0.004) and velocity (p = 0.007) decrement but not in maximal opening velocity. A significant relationship between the motor score from the Movement Disorders Society - Unified Parkinson's Disease Rating Scale and finger tapping decrement was shown for both patient groups, ie RBD (r = 0.36, p = 0.02) and PD (r = 0.60, p = 0.002). ConclusionsIn our group of RBD patients we demonstrated amplitude decrement of repetitive movements, which may correspond with prodromal bradykinesia. Our findings suggest instrumental analysis of finger tapping abnormalities as a potential novel clinical marker reflecting subclinical motor disturbances in RBD.

Predicting alpha-synuclein pathology by REM sleep behavior disorder diagnosis

Inability to accurately diagnose Lewy type alpha-synucleinopathy (LTS) pre-mortem has been a major obstacle to clinical care and research. Probable REM sleep behavior disorder (PRBD) diagnosed with support of instruments such as the Mayo Sleep Questionnaire (MSQ) may provide a cost effective means of predicting LTS. Since 2007, 602 subjects in the Arizona Study of Aging and Neurodegenerative Disorders had clinician assessment for PRBD (298 with, 304 without support of the MSQ), completed cognitive and movement examinations, and had neuropathological assessment. Mean age at death was 84.8 years. Histological evidence of LTS was found in 80/101(79.2%) cases with PRBD and 198/501 (39.5%) without PRBD (p < 0.001). Overall sensitivity for predicting LTS by PRBD diagnosis was 28.8%, specificity 93.5%, positive predictive value (PPV) 79.2%, negative predictive value (NPV) 60.5%. Diagnosis of PRBD was less frequently present in subjects without LTS [4/105 (3.8%) of healthy controls, 42/255 (16.5%) AD, 2/33 (6.1%) progressive supranuclear palsy (PSP) without LTS] than in subjects with LTS [11/46 (23.9%) DLB, 58/104 (55.8%) PD, and 4/16 (25.0%) PSP with LTS.] PRBD was not present in any of 46 subjects with incidental Lewy body disease (ILBD). MSQ-supported diagnosis of PRBD appears useful for predicting LTS in manifest neurodegenerative disease, but not necessarily ILBD. Additional prospective autopsy research, including well-characterized polysomnogram-confirmed RBD subjects, is needed to elucidate the earliest tissue abnormalities in the “idiopathic” (premotor/pre-dementia) stage of RBD.

Personality and addictive behaviours in early Parkinson's disease and REM sleep behaviour disorder

IntroductionChanges in personality have been described in Parkinson's disease (PD), with suggestion that those with established disease tend to be risk averse with a disinclination for addictive behaviour. However, little is known about the earliest and prodromal stages. Personality and its relationship with addictive behaviours can help answer important questions about the mechanisms underlying PD and addiction. Methods941 population-ascertained PD subjects within 3.5 years of diagnosis, 128 patients with rapid eye movement sleep behaviour disorder (RBD) and 292 control subjects were fully characterised for motor symptoms, non-motor symptoms and across the following 5 personality domains: 1) neuroticism 2) extraversion 3) conscientiousness 4) agreeableness 5) openness using the Big Five Inventory. ResultsPatients with early PD were more neurotic (p < 0.001), less extraverted (p < 0.001) and less open than controls (p < 0.001). RBD subjects showed the same pattern of being more neurotic (p < 0.001), less extraverted (p = 0.03) and less open (p < 0.001). PD patients had smoked less (p = 0.02) and drunk less alcohol (p = 0.03) than controls, but caffeine beverage consumption was similar. Being more extraverted (p < 0.001), more open (p < 0.001), and less neurotic (p < 0.001) predicted higher alcohol use, while being more extravert (p = 0.007) and less agreeable (p < 0.001) was associated with smoking more. ConclusionsA similar pattern of personality changes is seen in PD and RBD compared to a control population. Personality characteristics were associated with addictive behaviours, suggestive of a common link, but the lower rates of addictive behaviours before and after the onset of motor symptoms in PD persisted after accounting for personality.

REM Sleep Behavior Disorder: a Prodromal Synucleinopathy

Rapid eye movement sleep behavior disorder (RBD) is an abnormal condition that constitutes dream enactment behavior occurring during rapid eye movement (REM) phase sleep with loss of normal muscular atonia. Idiopathic RBD is a recognized risk factor for the development of alpha-synuclein neuropathology, often referred to as Lewy body disorders (LBD) like Parkinson disease, multiple system atrophy and dementia with Lewy bodies, with conversion rates of 80–90 % over a lifetime. In the past decade, studies have described multiple features of idiopathic RBD subjects that resemble patients with alpha-synucleinopathies, with specific abnormalities in olfaction, vision, gait, cognition, autonomic dysfunction, impaired cortical activity, and dopaminergic abnormalities in neuroimaging, leading to the idea that idiopathic RBD is a prodromal synucleinopathy that can precede neurodegenerative disease by decades.

Quantitative assessment of motor speech abnormalities in idiopathic rapid eye movement sleep behaviour disorder

ObjectivePatients with idiopathic rapid eye movement sleep behaviour disorder (RBD) are at substantial risk for developing Parkinson's disease (PD) or related neurodegenerative disorders. Speech is an important indicator of motor function and movement coordination, and therefore may be an extremely sensitive early marker of changes due to prodromal neurodegeneration. MethodsSpeech data were acquired from 16 RBD subjects and 16 age- and sex-matched healthy control subjects. Objective acoustic assessment of 15 speech dimensions representing various phonatory, articulatory, and prosodic deviations was performed. Statistical models were applied to characterise speech disorders in RBD and to estimate sensitivity and specificity in differentiating between RBD and control subjects. ResultsSome form of speech impairment was revealed in 88% of RBD subjects. Articulatory deficits were the most prominent findings in RBD. In comparison to controls, the RBD group showed significant alterations in irregular alternating motion rates (p = 0.009) and articulatory decay (p = 0.01). The combination of four distinctive speech dimensions, including aperiodicity, irregular alternating motion rates, articulatory decay, and dysfluency, led to 96% sensitivity and 79% specificity in discriminating between RBD and control subjects. Speech impairment was significantly more pronounced in RBD subjects with the motor score of the Unified Parkinson's Disease Rating Scale greater than 4 points when compared to other RBD individuals. ConclusionSimple quantitative speech motor measures may be suitable for the reliable detection of prodromal neurodegeneration in subjects with RBD, and therefore may provide important outcomes for future therapy trials.

REM sleep behavioral events (RBE): a new marker for neurodegeneration in early parkinson’s disease?

To analyze potential markers in sleep for early recognition of neurodegenerative disease in newly diagnosed, unmedicated patients with Parkinson’s disease (PD) compared to controls. Video-polysomnography (vPSG) was available in 158 newly diagnosed, unmedicated PD patients and 110 healthy age-, gender- and education-matched controls (HC). REM sleep was analyzed for REM without atonia (RWA) and studied by review of time-synchronized video. Motor behaviors and/or vocalizations in REM sleep with a purposeful component other than comfort moves were identified as REM sleep behavioral events (RBE). Two or more events had to be present to be classified as “RBE positive”. RBE subjects included RBD and non-RBD subjects based upon the presence or absence of RWA >18.2%. RBE were detected in 81/158 de novo PD patients (51%) and 17/110 HC (15%) ( p < 0.001). RBD was identified in 40/81 RBE positive PD patients (25% of all PD patients) and 2/17 RBE positive HC (2% of all controls). RBE positive patients showed no specific motor or neuropsychological features compared to RBE negative patients. PD patients and HC with RBE had more REM sleep ( p = 0.002) and a higher periodic leg movements in sleep index ( p = 0.022) compared to subjects without RBE. This first description of RBE shows it occurs more frequently in de novo PD patients than in HC and may be an early sign of neurodegeneration and precede RBD. There is no specific phenotype of PD associated with newly defined RBE or RBD at this early stage. The authors would like to thank Arthur Walters, Department of Neurology, Division of Sleep Medicine, Vanderbilt University, Nashville, Tennessee, USA for his most helpful advice.

Fight or flight? Dream content during sleepwalking/sleep terrors vs rapid eye movement sleep behavior disorder

Dreams enacted during sleepwalking or sleep terrors (SW/ST) may differ from those enacted during rapid eye movement sleep behavior disorder (RBD). Subjects completed aggression, depression, and anxiety questionnaires. The mentations associated with SW/ST and RBD behaviors were collected over their lifetime and on the morning after video polysomnography (PSG). The reports were analyzed for complexity, length, content, setting, bizarreness, and threat. Ninety-one percent of 32 subjects with SW/ST and 87.5% of 24 subjects with RBD remembered an enacted dream (121 dreams in a lifetime and 41 dreams recalled on the morning). These dreams were more complex and less bizarre, with a higher level of aggression in the RBD than in SW/ST subjects. In contrast, we found low aggression, anxiety, and depression scores during the daytime in both groups. As many as 70% of enacted dreams in SW/ST and 60% in RBD involved a threat, but there were more misfortunes and disasters in the SW/ST dreams and more human and animal aggressions in the RBD dreams. The response to these threats differed, as the sleepwalkers mostly fled from a disaster (and 25% fought back when attacked), while 75% of RBD subjects counterattacked when assaulted. The dreams setting included their bedrooms in 42% SW/ST dreams, though this finding was exceptional in the RBD dreams. Different threat simulations and modes of defense seem to play a role during dream-enacted behaviors (e.g., fleeing a disaster during SW/ST, counterattacking a human or animal assault during RBD), paralleling and exacerbating the differences observed between normal dreaming in nonrapid eye movement (NREM) vs rapid eye movement (REM) sleep.

Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease

To investigate the frequency and subtypes of mild cognitive impairment (MCI) in idiopathic rapid eye movement sleep behavior disorder (RBD) and Parkinson's disease (PD) in association with RBD. One hundred and twelve subjects without dementia or major depression including 32 idiopathic RBD patients, 22 PD patients with polysomnography-confirmed RBD, 18 PD patients without RBD, and 40 healthy control subjects, underwent a comprehensive neuropsychological evaluation. We compared the proportion of patients with MCI between groups using standard diagnostic criteria. MCI was found in 50% of idiopathic RBD patients and 73% of PD patients with RBD. In contrast, only 11% of PD patients without RBD and 8% of control subjects had MCI. The presence of MCI was significantly greater in idiopathic RBD patients and PD patients with RBD than in PD patients without RBD and control subjects. PD patients with RBD also performed worse than idiopathic RBD patients on neuropsychological tests assessing visuoconstructional and visuoperceptual abilities. In both its association with PD and its idiopathic form, RBD is an important risk factor for MCI. Except for visuoconstructional and visuoperceptual problems, RBD may be an important determinant of cognitive impairment in PD. Ann Neurol 2009;66:39-47.

123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder.

RBD is considered to be a manifestation of an evolving synucleinopathy, such as Parkinson disease (PD), dementia of Lewy bodies (DLB), and multiple system atrophy (MSA). We tested whether the degree of accumulation of cardiac 123I-MIBG scintigraphy can distinguish the clinical syndromes associated with Lewy body-related disease from the syndrome of PSP (a tauopathy) and MSA. Cross-sectional. University-based sleep disorders laboratory. Subjects comprised 95 patients (31, idiopathic RBD; 26, PD; 10, MSA; 6, DLB; 13, progressive supranuclear palsy [PSP]) and 9 control subjects. To compare tracer uptake of cardiac 123I-MIBG between idiopathic RBD, PD, MSA, DLB, and PSP and control subjects. Cardiac 123I-MIBG accumulation was evaluated by the heart/mediastinum (H/M) ratio. Mean value of the H/M ratio (early, delayed) was significantly reduced in patients with idiopathic RBD compared to MSA patients, PSP patients, control subjects (P < 0.001 in each group) and PD patients in early images (P < 0.05). There was a correlation between the H/M ratio and disease duration in the idiopathic RBD group. ROC analysis revealed that an H/M cut-off value of 1.9 was useful for differentiating RBD from MSA and PSP as well as distinguishing control subjects from those with RBD in both early and delayed images. Cardiac 123I-MIBG findings are similar among idiopathic RBD and the syndromes of PD and DLB, but differ from those of PSP and MSA.

Perception and production of facial and prosodic emotions by chronic CVA patients

Variable etiology, limited testing of emotions and inclusion of patients in acute and chronic phases have made it difficult to specify the extent of right hemisphere involvement in the processing of emotional material. In addition, there is an absence of data concerning CVA patients’ long-term abilities to process emotional information. Two groups of subjects with unilateral brain damage (15 RBD, 17 LBD), matched for chronicity (minimum 12 months post-CVA), etiology (ischemic CVA), duration of hospitalization and other variables, and an appropriate control group participated in two experiments to address these concerns. In the first experiment, subjects were given a series of tasks (discrimination, identification, imitation, production on request) to assess their processing of facial expressions of the six universal emotions [P. Ekman, W. Friesen, Unmasking the face, Prentice-Hall, Englewood Cliffs, 1975]. The results showed that three emotions (surprise, happiness, fear) discriminate between RBD and LBD patients and controls, with RBD subjects performing worse than the other groups on the identification task only. Using tasks of the same nature, the second experiment investigated the processing of emotional prosody. The results showed that three emotions (fear, sadness, anger) discriminate between RBD and LBD patients and controls, with RBD subjects again performing worse than the others on the discrimination, imitation and production on request tasks. LBD subjects performed as well as normal controls on almost all tasks. The RBD subjects were the only ones who showed relatively consistent impairment in the processing of both facial and prosodic emotional information. Taken together, these data strongly suggest that the right hemisphere is preferentially involved in processing emotional information in the chronic phase of brain damage.

Dot counting by brain damaged subjects

In this study, we examine how brain damaged adults (aphasics, right-brain lesioned subjects (RBD), and demented subjects) perform a basic education skill: determining the cardinality of different sets of objects (dots). The RBD subjects encountered more difficulty with the spatial correspondence components of the task (correct pointing to the dots), while the aphasics experienced more difficulty with the verbal components (the production of the correct number-word sequence). The deficit evidenced by the demented patients was less systematic. However, qualitative analyses of patients' behavior suggested an organization that tended to minimize the impact of their cognitive deficits on the object-counting task, and an analysis of their counting indicates that the basic counting principles proposed by Gelman (1982) and Fuson (1988) may be preserved.

Familiar voice recognition and unfamiliar voice discrimination are independent and unordered abilities

One‐hundred and ten normal and thirty‐two brain‐damaged (BD) subjects were tested on voice discrimination and voice recognition protocols. The recognition task included samples of famous male voices in a multiple‐choice format; the discrimination test consisted of pairs of male voices in a same‐different task. Three findings suggest a dissociation between the two abilities. (1) Scores on the two tasks were only slightly correlated in normal subjects and were not significantly correlated in BD subjects, suggesting no obligatory relationship between performance on one task and performance on the other. (2) RBD subjects performed significantly less well than normal controls in recognition, while LBD subjects did not differ from normals; brain damage in either hemisphere affected discrimination abilities. (3) Nearly half of the BD subjects showed very large discrepancies between scores on the tasks, with chance performance on one alongside normal scores on the other. These asymmetries in performance occurred in both directions, indicating that discrimination and recognition are independent, unordered processes. Examination of CAT scans suggests that voice recognition is impaired only in right‐posterior BD, while voice discrimination is impaired in damage to the temporal lobes on either side.